Botanical-drug Interactions Research Articles

Botanical-induced toxicity: Liver injury and botanical-drug interactions. A report on a society of Toxicology Annual Meeting symposium

Botanical supplements and herbal products are widely used by consumers for various purported health benefits, and their popularity is increasing. Some of these natural products can have adverse effects on liver function and/or interact with prescription and over-the-counter (OTC) medications. Ensuring the safety of these readily available products is a crucial public health concern; however, not all regulatory authorities require premarket safety review and/or testing. To address and discuss these and other emerging needs related to botanical safety, a symposium was held at the Society of Toxicology Annual Meeting in Salt Lake City (UT) on March 11, 2024. The symposium addressed the latest research on botanical-induced liver toxicity and botanical-drug interactions, including new approach methods to screen for toxicity, challenges in assessing the safety of botanicals, and relating human adverse events to specific products. The presentations and robust panel discussion between the speakers and audience highlighted the need for further research and collaboration to improve the safety of botanical supplements and herbal products, with the ultimate goal of protecting consumer health. Although utility of many of the modern tools presented in the symposium requires further study, the synergistic efforts of diverse experts hold promise for effective prediction and evaluation of botanical-induced hepatotoxicity and botanical-drug interaction potential.

A comparative metabolomics analysis of Açaí (Euterpe oleracea Mart.) fruit, food powder, and botanical dietary supplement extracts.

Euterpe oleracea Mart. (açaí) is a botanical of interest to many who seek functional foods that provide antioxidant and anti-inflammatory properties. Cancer patients are increasingly taking botanical dietary supplements containing açaí to complement their conventional therapeutics, which may lead to serious adverse events. Before testing our açaí extracts in vitro for botanical-drug interactions, the goal is to chemically characterize our extracts for compounds whose biological activity in açaí is unknown. The objective of this work was to develop a chemical fingerprinting method for untargeted characterization of açaí samples from a variety of sources, including food products and botanical dietary supplement capsules, made with multiple extraction solvents. An optimized LC-MS method was generated for in-depth untargeted fingerprinting of chemical constituents in açaí extracts. Statistical analysis models were used to describe relationships between the açaí extracts based on molecular features found in both positive and negative mode ESI. In an attempt to elucidate the differences in metabolites among açaí extracts from different cultivars, we identified or tentatively identified 173 metabolites from the 16 extracts made from 6 different sources. Of these compounds, there are 138 reported in açaí for the first time. Statistical models showed similar yet distinct differences between the extracts tested based on the polarity of compounds present and the origin of the source material. A high-resolution mass spectrometry method was generated that allowed us to greatly characterize 16 complex extracts made from different sources of açaí with different extraction solvent polarities.

Examining dietary supplements containing Euterpe oleracea Mart. (açaí) for potential botanical-drug interactions involving CYP3A4 inhibition

BackgroundBotanical dietary supplements (BDS) are consumed more by cancer patients than otherwise healthier patients to alleviate side effects of chemotherapy drugs or increase quality of life. The enzyme responsible for the metabolism of most anticancer drugs is CYP3A4, an enzyme predominantly located in the liver. HypothesisOur research team examined the potential risk between CYP3A4-interactive cancer drugs and Euterpe oleracea Mart. (açaí) berry and found that the compounds that passively and non-passively diffused from methanol açaí extract displayed significant inhibition of liver CYP3A4 – suggesting the potential for interactions between açaí and drugs metabolized by CYP3A4 if used synchronously. This study aims to identify the compounds responsible for the CYP3A4 inhibition using the newly automated Bioactivity – Global Natural Product Social Molecular Networking (GNPS) tool. MethodsDietary supplement capsules from two manufacturers (F1 and F2) containing aqueous extracts of açaí fruits were extracted separately by methanol (ME) and acidic methanol (AC) and standardized to cyanidin-3-O-glucoside (CG) concentration at a human-relevant dose. After solvent removal, a parallel artificial membrane permeability assay (PAMPA) was utilized to filter intestinal passive diffusion of the four extract constituents so that compounds could be tested for inhibition of hepatic CYP3A4. Passively and non-passively diffused constituents of extracts from PAMPA assays were injected into the liquid chromatography-mass spectrometry (LC–MS) and characterized for visualization and comparison of chemical entities. To elucidate the non-passively diffused compounds responsible for significant CYP3A4 inhibition, the Bioactivity – GNPS tool was used to hypothesize which compounds within the formulation extract were potentially active to accelerate their identification. ResultsThere was no significant inhibition of CYP3A4 by passively diffused constituents for any extract. There was, however, significant inhibition by non-passively diffused constituents of both F1ME and F1AC extracts with 50 % CYP3A4 inhibition at the donor compartment concentrations 5.764 and 15.58 ng/ml CG, respectively. Six compounds were predicted to be inhibitors of CYP3A4 from methanol F1 extract, including betaine and 5 unknown compounds. ConclusionThis indicates that BDS containing açaí may not inhibit CYP3A4 through passively diffused compounds. Compounds from açaí BDS that inhibit CYP3A4 may be absorbed through other mechanisms, such as transporters.

Cannabis and the Cancer Patient

AbstractSession 2 of the National Cancer Institute’s Cannabis, Cannabinoids, and Cancer Research Workshop opened with testimony from a lymphoma survivor who detailed medicinal cannabis-related improvements in nausea, low appetite, insomnia, and mental health and the limited clinical counsel she received regarding cannabis use. Discussion next turned to the evolution of the legal landscape of cannabis in the United States, one in which state and federal laws frequently conflict and the Controlled Substance Act renders cannabis Schedule I. This legal climate creates conundrums for US medicinal cannabis researchers who contend with limited funding opportunities, avenues to source trial drug, and procedural red tape and for oncology clinicians who recommend medicinal cannabis to patients with some frequency while perceiving themselves as ill equipped to make such clinical recommendations. Ultimately, it creates challenges for cancer patients who find themselves turning to nonmedical and anecdotal information sources. The risks of cannabis use by the cancer patient were discussed next. These include infection, pharmacodynamic and pharmacokinetic drug-botanical interactions, cyclic nausea and vomiting, e-cigarette or vaping product use–associated illness, legal issues, and high cost. The session concluded with a broad survey of the research supporting oncologic cannabinoid use, conclusive evidence for chemotherapy-induced nausea and vomiting, and suggestive evidence for cancer-related pain.

Oral epigallocatechin gallate reduces intestinal nadolol absorption via modulation of Oatp1a5 and Oct1 transcriptional levels in spontaneously hypertensive rats

BackgroundConcurrent use of epigallocatechin-3-gallate (EGCG) and medication may lead to botanical-drug interactions, subsequently therapeutic failure or drug toxicity. It has been reported that EGCG reduces plasma nadolol bioavailability in normotensive models. Nevertheless, evidence on the effects of EGCG on hypertensive model, and the possible underlying mechanism have not been elucidated. ObjectivesThis study aims (i) to investigate the effects of EGCG on nadolol pharmacokinetics (maximum plasma concentration, time to achieve maximum concentration, area under the time-plasma concentration curve, plasma half-life and total clearance) and subsequently its impact on blood pressure control; and (ii) to identify transcriptional regulatory roles of EGCG on the nadolol intestinal and hepatic drug-transporters in SHR. MethodsMale SHR were pre-treated with a daily dose of EGCG (10 mg/kg body weight, i.g.) for 13 days. On day-14, a single dose of nadolol (10 mg/kg body weight) was given to the rats 30 min after the last dose of EGCG administration. Systolic blood pressure (SBP) was measured at 6-h and 22-h post-nadolol administration. Plasma and urinary nadolol concentrations were quantified using high-performance liquid chromatography, and pharmacokinetic parameters were analyzed by using non-compartmental analysis. Hepatic and ileal Oatp1a5, P-gp, and Oct1 mRNA expressions were determined by real-time PCR. ResultsSBP of SHR pre-treated with EGCG and received nadolol was significantly higher than those which were not pre-treated with EGCG but received nadolol. Pre-treatment of EGCG resulted in a marked reduction of plasma nadolol maximum concentration (Cmax) and area under the time-plasma concentration curve (AUC) by 53% and 51% compared to its control. The 14-day treatment with oral EGCG led to a significant downregulation of mRNA levels of ileal Oatp1a5, P-gp, and Oct1 genes by 4.03-, 8.01- and 4.03-fold; and hepatic P-gp, and Oct1 genes by 2.61- and 2.66-fold. ConclusionThese data concluded that exposure to EGCG could lead to reduced nadolol bioavailability and therefore, uncontrolled raised blood pressure and higher risks of cardiovascular events. Our data suggest that the reduced nadolol bioavailability is associated with the downregulation of ileal Oatp1a5 and Oct1 mRNA levels that subsequently lead to poor absorption of nadolol to the systemic circulation.

Safety of Cranberry: Evaluation of Evidence of Kidney Stone Formation and Botanical Drug-Interactions.

Cranberry is a popular ingredient in dietary supplements in the U. S. and is commonly used for preventing urinary tract infections. Because of its popularity in dietary supplements, the U. S. Pharmacopeial Convention has developed quality standards for cranberry ingredients. The purpose of this review was to determine if there are safety issues that should preclude the admission of cranberry ingredients from the development of U. S. Pharmacopeial Convention quality standards. Based on the totality of the data, the U. S. Pharmacopeial Convention concluded that cranberry ingredients are not known to be associated with serious risks to human health when consumed properly in dietary supplements and therefore were admitted for standard development. Although published clinical and animal data indicated that cranberry is not associated with serious adverse effects, interactions with warfarin and kidney stone formation were identified as potential risks. Studies have reported contradictory data regarding the role of cranberry in kidney stone formation, with some reports suggesting cranberry is associated with a reduced risk of kidney stones. Interactions with warfarin were not associated with moderate intakes of cranberry juice (240 - 480 mL). Some reports suggested that the potential for warfarin interactions requires excessive intakes of cranberry juice (1 - 2 L/day) or cranberry extracts (3000 mg/day). Cases of warfarin interactions with cranberry have mostly involved patients with serious illnesses and/or individuals taking concomitant medications. Based on these findings, the U. S. Pharmacopeial Convention concluded that the use of cautionary labeling statements regarding interactions with warfarin or kidney stone formation is not necessary in the development of quality standards for cranberry ingredients.

Epigallocatechin Gallate Supplementation Suppressed Antihypertensive Effect of Nadolol in Spontaneously Hypertensive Rats

Background: Concurrent use of Camellia sinensis (green tea) and its main constituent, EGCG may lead to botanical-drug interactions and therefore therapeutic failure or drug toxicity. It has been reported that EGCG reduced plasma nadolol, an antihypertensive drug concentration in a normotensive model. Nevertheless, evidence on the effect of EGCG on pharmacological action of nadolol in hypertensive model has not been elucidated.

Botanical Product Use Among Multiple Myeloma Patients in Commercial Drug Trials

Botanical medication use is frequently reported among patients with cancer, including those undergoing treatment. The use of botanical medicines among patients with solid tumors has been frequently studied and concerns raised about the potential for botanical-drug interactions. To date, limited information exists about botanical medicine use for multiple myeloma patients. Furthermore, relatively few studies of botanical medicine use among cancer patients enrolled in commercial clinical trials have been undertaken, despite the importance of these trials for establishing the safety and efficacy of new drugs. We sought to describe botanical concomitant medication use among patients with multiple myeloma enrolled on commercial trials of anti-myeloma investigational products, the content of trial protocols regarding concomitant botanical medications, and the potential for botanical-drug interactions. Using internal FDA databases, we identified eight randomized, multi-arm trials of products submitted to FDA for regular approval from 2015 to 2018 with concomitant medication datasets that used the standard World Health Organization Anatomical Therapeutic Chemical (WHO ATC) classification. Botanical products were identified by reviewing concomitant medications from the ATC classes of unassigned/blank, all other therapeutic products, all other non-therapeutic products, and unspecified botanical and traditional medications. Frequently prescribed botanical laxatives such as senna were excluded. We pooled data across the eight trials and compared botanical use by region, disease characteristics, and sociodemographic characteristics. We also assessed the types of botanical products used. Products were categorized into types using the plant name identified from the dictionary or preferred name, where available. We also evaluated whether trial protocols provided guidelines regarding botanical medication use. Finally, we assessed if any of the products could affect CYP3A4 by reviewing information from the Memorial Sloan Kettering Cancer Center's online database for integrative medicine and the Natural Medicines online database for integrative therapies. We evaluated data from 4,712 patients recruited from 40 countries in the pooled intention-to-treat (ITT) populations, of whom 303 (6.4%) used botanical products at any time (on/off trial) and 257 (5.5%) used botanical products while on trial. Nearly all patients (91%) who used botanical products used just a single type of botanical product. The maximum number of products used per patient was three. Patients who used botanical products and those who did not were similar in terms of age, sex, and prior lines of therapy. However, use varied by region. In Asia, 27% of patients used botanicals, compared to 10% in North America and Oceania and 3% in Western Europe. Many botanical medications (49% of all products) could not be classified by plant name. Frequently used medications included ginkgo biloba (6% of all products), milk thistle (5% of all products), and saw palmetto (4% of all products). All trial protocols provided guidelines regarding the use of concomitant medications. Specifically, the protocols included the need to record any concomitant medications and discussed which medications and/or medication classes were required, allowed, and prohibited/restricted. In all protocols we examined, botanical products were not explicitly mentioned in the discussion of concomitant medications. Of the 55 botanical products that could be classified by plant names, preliminary review identified 15 products (27%) that had possible interactions with CYP3A4, although for many of these the evidence was based on in vitro or animal studies. One product, camellia sinensis, was noted to inhibit bortezomib, which was an active agent used in several of the included trials. In conclusion, multiple myeloma patients enrolled in commercial drug trials rarely use botanical medications, although use is more common in some regions. Although use is infrequent, sponsors may wish to consider inclusion of guidance regarding botanical medications in their protocol section relating to concomitant medications, particularly because of the potential for botanical-drug interaction. Of concern is the inability to group many products by plant name, which may obscure the identification of any potential interactions with drugs. Disclosures No relevant conflicts of interest to declare.

Screening for CYP3A4 inhibition and induction coupled to parallel artificial membrane permeability assay (PAMPA) for prediction of botanical-drug interactions: The case of açaí and maca

BackgroundThe consumption of botanical dietary supplements (BDS) is a common practice among the US population. However, the potential for botanical-drug interactions exists, and their mechanisms have not been thoroughly studied. CYP3A4 is an important enzyme that contributes to the metabolism of about 60% of clinically used drugs. PurposeTo investigate the potential for botanical-drug interactions of Lepidium meyenii Walpers (maca) root and Euterpe oleracea Mart. (açaí) berries, two commonly used BDS, when co-administered with CYP3A4-metabolized drugs. MethodsIn an attempt to decrease the general discrepancy between in vivo and in vitro studies, the absorption profiles, particularly for passive diffusion, of plant extracts were investigated. Specifically, the parallel artificial membrane permeability assay (PAMPA) model was utilized to simulate intestinal filtration of passively diffused constituents of açaí and maca extracts. These were subsequently screened for in vitro liver CYP3A4 inhibition and induction. In the inhibition assay, midazolam was used as the probe substrate on genotyped human liver microsomes (CYP3A5 null), and the production of its 1′-substituted metabolite when co-cultured with extract treatments was monitored. In the induction assay, extract treatments were applied to human primary hepatocytes, and quantitative PCR analysis was performed to determine CYP3A4 mRNA expression. ResultsPassively diffused constituents of the methanol açaí extract (IC50 of 28.03 µg/µl) demonstrated the highest inhibition potential, and, at 1.5 µg/µl, induced significant changes in CYP3A4 gene expression. The composition of this extract was further investigated using the chemometric tool Mass Profiler Professional (MPP) on liquid chromatography-mass spectroscopy (LC-MS) data. Subsequently, five compounds of interest characterized by high abundance or high permeability were extracted for further study. This included efforts in effective passive permeability determination and structural elucidation by tandem mass spectrometry (MS/MS). ConclusionThe passively absorbable portion of a methanol açaí extract exhibited inhibition and induction effects on CYP3A4 suggesting the potential to produce botanical-drug interactions.

An Evaluation of Potential Inhibition of CYP3A4/5 and CYP2C9 Enzymatic Activity by Boswellia serrata Extract

Abstract Introduction: As the use of dietary supplements increases, botanical–drug interaction (BDI) potentials should be evaluated. Boswellia serrata extract (BSE) is traditionally used as an anti...

Follow that botanical: Challenges and recommendations for assessing absorption, distribution, metabolism and excretion of botanical dietary supplements

Botanical dietary supplements are complex mixtures containing one or more botanical ingredient(s), each containing numerous constituents potentially responsible for its purported biological activity. Absorption, distribution, metabolism, and excretion (ADME) data are critical to understand the safety of botanical dietary supplements, including their potential for pharmacokinetic botanical-drug or botanical-botanical interactions. However, ADME data for botanical dietary supplements are rarely available and frequently inadequate to characterize their fate in vivo. Based on an assessment of the current status of botanical dietary supplements ADME research, the following key areas are identified that require robust data for human safety assessment: 1) phytochemical characterization including contaminant analysis and botanical authentication; 2) in vitro and/or in vivo data for identifying potential botanical-botanical or botanical-drug interactions and active/marker constituents; 3) robust ADME study design to include systemic exposure data on active/marker constituents using traditional or novel analytical chemistry and statistical approaches such as poly-pharmacokinetics; and 4) investigation of human relevance. A case study with Ginkgo biloba extract is used to highlight the challenges and proposed approaches in using ADME data for human safety assessment of botanical dietary supplements.

A Tiered Approach for the Evaluation of the Safety of Botanicals Used as Dietary Supplements: An Industry Strategy.

Exposure to botanicals in dietary supplements is increasing across many geographies; with increased expectations from consumers, regulators, and industry stewards centered on quality and safety of these products. We present a tiered approach to assess the safety of botanicals, and an in silico decision tree to address toxicity data gaps. Tier 1 describes a Threshold of Toxicologic Concern (TTC) approach that can be used to assess the safety of conceptual levels of botanicals. Tier 2 is an approach to document a history of safe human use for botanical exposures higher than the TTC. An assessment of botanical‐drug interaction (BDI) may also be necessary at this stage. Tier 3 involves botanical chemical constituent identification and safety assessment and the in silico approach as needed. Our novel approaches to identify potential hazards and establish safe human use levels for botanicals is cost and time efficient and minimizes reliance on animal testing.

Cytochrome P450 inhibition by three licorice species and fourteen licorice constituents

The potential of licorice dietary supplements to interact with drug metabolism was evaluated by testing extracts of three botanically identified licorice species (Glycyrrhiza glabra L., Glycyrrhiza uralensis Fish. ex DC. and Glycyrrhiza inflata Batalin) and 14 isolated licorice compounds for inhibition of 9 cytochrome P450 enzymes using a UHPLC-MS/MS cocktail assay. G. glabra showed moderate inhibitory effects against CYP2B6, CYP2C8, CYP2C9, and CYP2C19, and weak inhibition against CYP3A4 (testosterone). In contrast, G. uralensis strongly inhibited CYP2B6 and moderately inhibited CYP2C8, CYP2C9 and CYP2C19, and G. inflata strongly inhibited CYP2C enzymes and moderately inhibited CYP1A2, CYP2B6, CYP2D6, and CYP3A4 (midazolam). The licorice compounds isoliquiritigenin, licoricidin, licochalcone A, 18β-glycyrrhetinic acid, and glycycoumarin inhibited one or more members of the CYP2C family of enzymes. Glycycoumarin and licochalcone A inhibited CYP1A2, but only glycycoumarin inhibited CYP2B6. Isoliquiritigenin, glabridin and licoricidin competitively inhibited CYP3A4, while licochalcone A (specific to G. inflata roots) was a mechanism-based inhibitor. The three licorice species commonly used in botanical dietary supplements have varying potential for drug-botanical interactions as inhibitors of cytochrome P450 isoforms. Each species of licorice displays a unique profile of constituents with potential for drug interactions.

Safety of Combined Treatment With Monoclonal Antibodies and Viscum album L Preparations.

Combination strategies involving chemotherapy and monoclonal antibodies (mAb) are commonly used in attempts to produce better clinical outcomes. This practice has led to new and ongoing toxicities that may lead to reductions in dose or noncompliance, limiting the effectiveness of treatment. Viscum album L (VA) preparations are widely used in Europe as additive therapy and have been associated with reduced chemotherapy-related adverse reactions and increased health-related quality of life. Concomitant VA therapy might also reduce toxicity related to mAb. This retrospective study investigated the safety of combined treatment with VA and mAb in cancer patients. A total of 43 patients had combined therapy (474 exposures); 12 had VA without mAb (129 exposures), and 8 had mAb without VA (68 exposures). Most patients (89.3%) received concomitant chemotherapy or supportive therapies. A total of 34 patients (60.7%) experienced 142 adverse events (AEs). Leucopenia (14.1% of all events), acneiform rash (8.5%), and stomatitis (6.3%) occurred most frequently. Longitudinal logistic regression analysis suggested a nearly 5 times higher odds of experiencing an AE following treatment with mAb compared with mAb plus VA (95% CI = 1.53-16.14). Our results, together with theoretical consideration of potential botanical-drug interactions, suggest that combined treatment with VA and mAb is safe.

Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements.

The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug-botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John's wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug-botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug-botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism.

High-Throughput Cytochrome P450 Cocktail Inhibition Assay for Assessing Drug-Drug and Drug-Botanical Interactions.

Detection of drug-drug interactions is essential during the early stages of drug discovery and development, and the understanding of drug-botanical interactions is important for the safe use of botanical dietary supplements. Among the different forms of drug interactions that are known, inhibition of cytochrome P450 (P450) enzymes is the most common cause of drug-drug or drug-botanical interactions. Therefore, a rapid and comprehensive mass spectrometry-based in vitro high-throughput P450 cocktail inhibition assay was developed that uses 10 substrates simultaneously against nine CYP isoforms. Including probe substrates for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and two probes targeting different binding sites of CYP3A4/5, this cocktail simultaneously assesses at least as many P450 enzymes as previous assays while remaining among the fastest due to short incubation times and rapid analysis using ultrahigh pressure liquid chromatography-tandem mass spectrometry. The method was validated using known inhibitors of each P450 enzyme and then shown to be useful not only for single-compound testing but also for the evaluation of potential drug-botanical interactions using the botanical dietary supplement licorice (Glycyrrhiza glabra) as an example.

Development of Safe and Effective Botanical Dietary Supplements.

Regulated differently than drugs or foods, the market for botanical dietary supplements continues to grow worldwide. The recently implemented U.S. FDA regulation that all botanical dietary supplements must be produced using good manufacturing practice is an important step toward enhancing the safety of these products, but additional safeguards could be implemented, and unlike drugs, there are currently no efficacy requirements. To ensure a safe and effective product, botanical dietary supplements should be developed in a manner analogous to pharmaceuticals that involves identification of mechanisms of action and active constituents, chemical standardization based on the active compounds, biological standardization based on pharmacological activity, preclinical evaluation of toxicity and potential for drug–botanical interactions, metabolism of active compounds, and finally, clinical studies of safety and efficacy. Completing these steps will enable the translation of botanicals from the field to safe human use as dietary supplements.

Pharmacokinetic interactions between drugs and botanical dietary supplements

The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but under-investigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport and/or metabolism of pharmaceutical agents. Clinical trials of drug-botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive in vitro studies. For example, Phase I clinical trials have confirmed clinical observations and in vitro studies that St. John's wort (Hypericum perforatum) induces cytochrome P450 3A4/5, whereas Phase I studies did not substantiate in vitro predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. Here, we highlight discrepancies between in vitro and in vivo data concerning drug-botanical interactions and critically evaluate why some in vitro models overestimate or sometimes underestimate the potential for drug-botanical interactions. Gaps in our knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport and metabolism.

High-throughput cytochrome P450 inhibition cocktail assay for evaluating possible drug-botanical interactions: Application to licorice

High-throughput cytochrome P450 inhibition cocktail assay for evaluating possible drug-botanical interactions: Application to licorice

Development of safe and effective botanical dietary supplements

Regulated differently than drugs or foods, the market for botanical dietary supplements continues to grow worldwide. The recently implemented US FDA regulation that all botanical dietary supplements must be produced using Good Manufacturing Practice is an important step toward enhancing the safety of these products, but additional safeguards could be implemented, and unlike drugs, there are currently no efficacy requirements. To ensure a safe and effective product, botanical dietary supplements could be developed rigorously in a manner analogous to pharmaceuticals that involves identification of mechanisms of action and active constituents, chemical standardization based on the active compounds, biological standardization based on pharmacological activity, preclinical evaluation of toxicity and potential for drug-botanical interactions, metabolism of active compounds, and finally, clinical studies of safety and efficacy. Although not required, completing as many of these steps as possible would contribute to the translation of botanicals from the field to safe human use as dietary supplements.